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© 2000 American Society for Clinical Oncology Concomitant Chemoradiotherapy as Primary Therapy for Locoregionally Advanced Head and Neck CancerByFrom the Departments of Medicine (Section of Hematology/Oncology)Radiation and Cellular Oncology, and Surgery, Committee of Clinical Pharmacology, and Comprehensive Cancer Center, University of Chicago, and Departments of Medicine, Radiation Oncology, and Surgery, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL. Address reprint requests to Everett E. Vokes, MD, University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637; email evokes{at}medicine.bsd.uchicago.edu
PURPOSE: To achieve locoregional control of head and neck cancer, survival, and organ preservation using intensive concomitant chemoradiotherapy.
PATIENTS AND METHODS: This study was a phase II trial of chemoradiotherapy with cisplatin 100 mg/m2 every 28 days, infusional fluorouracil 800 mg/m2/d for 5 days, hydroxyurea 1 g orally every 12 hours for 11 doses, and radiotherapy twice daily at 1.5 Gy/fraction on days 1 through 5 (total dose, 15 Gy). Five days of treatment were followed by 9 days of rest, during which time patients received granulocyte colony-stimulating factor. Five cycles (three with cisplatin) were administered over 10 weeks (total radiotherapy dose, RESULTS: Seventy-six patients were treated (stage IV, 93%; N2, 54%; N3, 21%). At a median follow-up of 38 months, the 3-year progression-free survival is 72%, locoregional control 92%, systemic control 83%, and overall survival 55%. Toxicities included mucositis (grade 3, 45%; grade 4, 12%), neutropenia (grade 4, 39%), and thrombocytopenia (grade 4, 53%). Surgery at the primary site was performed in 13 patients, and 39 had neck dissection. A majority of patients declined adjuvant chemoprevention. Pharmacokinetic parameters were not prognostic of tumor control. Quality of life declined during treatment but returned from good to excellent by 12 months after treatment. CONCLUSION: Intensive concomitant chemoradiotherapy leads to high locoregional control and survival rates with organ preservation and a reversal of the historical pattern of failure (distant > locoregional). Surgery after concomitant chemoradiotherapy is feasible. Compliance with adjuvant chemoprevention is poor. Identification of less toxic regimens and improved distant disease control emerge as important future research goals.
TRADITIONAL THERAPY for locoregionally advanced squamous cell head and neck cancer has consisted of surgery and postoperative radiotherapy. Although this approach is curative in intent, a majority of patients die of locoregional recurrence. In addition, the frequently aggressive surgical procedures, though technically feasible, result in significant long-term anatomic, functional, and psychologic sequelae in the surviving patient.1-3 This has led to the development of organ-preserving treatment strategies.3-6 Patients with advanced-stage head and neck cancer are also at risk of developing distant metastases, though this occurs less frequently than does locoregional failure.7,8 Finally, surviving patients are at a lifelong risk of developing a second malignancy, which results from field carcinogenesis in the aerodigestive tract caused by long-term exposure to alcohol and tobacco, and need medical surveillance for other potentially related diseases.9,10 To improve head and neck cancer treatment outcomes, chemotherapy has been added to surgery and radiotherapy. A sequential approach, most often in the form of induction chemotherapy, has failed to improve survival rates.1-8,11 However, in large randomized studies, larynx preservation has been demonstrated to be feasible.3-6 Of interest, induction chemotherapy has also reduced the incidence of distant metastases as sites of first failure. However, because systemic failure affects only a small proportion of patients, this decrease is insufficient to increase survival rates in the absence of effective locoregional control. Concomitant chemoradiotherapy is conceptually supported by the natural history of head and neck cancer, which indicates a primary need to improve locoregional therapy and only a secondary need to improve systemic therapy. Concomitant chemoradiotherapy has frequently been studied in inoperable patients or in those with unresectable disease.12 Several recent studies and meta-analyses have indicated superior locoregional control and/or survival rates after concomitant chemoradiotherapy when compared with radiotherapy alone.11-20 Thus, a concomitant combined modality approach seems to be superior to both radiotherapy alone and the sequential multimodality therapy approach. Although the concomitant chemoradiotherapy approach has been studied frequently in patients with unresectable disease, its use with organ preservation as a clearly stated study end point has been rarely reported. Thus, an inclusive and comprehensive treatment plan for locoregionally advanced head and neck cancer will need to aim at increased locoregional control while attempting to preserve anatomically critical organs. It will also include systemic therapy to treat presumed microscopic disease, consider the use of chemopreventive agents in patients who have achieved complete remission, and provide medical management of the patient to treat coexisting medical conditions. At the University of Chicago and Northwestern University, we have a longstanding interest in the administration of multiagent chemotherapy with intensive radiotherapy for advanced head and neck cancer.21-25 We previously reported on the feasibility and activity of a regimen that consisted of infusional fluorouracil (5-FU), hydroxyurea, and concomitant radiotherapy (FHX) administered every other week.24,25 This alternating-week 5-FU–based chemoradiotherapy schedule had been defined previously in the phases I and II setting.26,27 We have also reported on the feasibility of adding cisplatin to the FHX regimen as a third, systemically active agent in head and neck cancer and of intensifying the radiotherapy fractionation schedule to a twice-daily schedule (C-FHX).28 We now report a long-term analysis of a phase II feasibility study in which the C-FHX regimen is used as primary therapy for previously untreated patients with locoregionally advanced head and neck cancer, followed by optional surgery and adjuvant chemoprevention. For chemoprevention, we chose the combination of cis-retinoic acid (CRA) and interferon alfa-2A (IFN) as described by Lippman et al.29
This study opened in September 1993 and closed to patient accrual in February 1996. Patients were entered at three participating institutions: the University of Chicago, Northwestern University, and Michael Reese Hospital. Eligible patients had locoregionally advanced stage IV carcinoma of the head and neck arising from the oral cavity, pharynx, larynx, paranasal sinuses, and cervical esophagus. Patients with stage III disease were eligible only if the primary site included the base of tongue or hypopharynx. All therapy was given with curative intent. Before study entry, the patients were evaluated by a multispecialty team composed of an attending surgeon, a radiation oncologist, and a medical oncologist. The timing and feasibility of surgery was determined in each patient before initiation of therapy. All patients were required to have histologic or cytologic confirmation of squamous cell carcinoma, mucoepidermal carcinoma, or lymphoepithelioma. The unequivocal demonstration of distant metastasis (M1) conferred ineligibility. Measurable disease was not required but was carefully documented when present. Patients had not received prior chemotherapy or radiotherapy and had a Cancer and Leukemia Group B performance status of 0 to 2. Baseline laboratory requirements included a WBC count greater than 3,500 cells/µL, an absolute neutrophil count greater than 1,500 cells/µL, and a platelet count  100,000 platelets/µL. Either the serum creatinine had to be  1.5 mg/dL or the calculated creatinine clearance had to exceed 50 mL/min. All patients signed institutional review board–approved informed consent forms.
Therapy Plan
Radiotherapy Guidelines Patients had complete dental evaluations and were simulated before the start of treatment with an appropriate immobilization device. Radiotherapy field sizes were determined at the time of simulation to treat gross disease and areas of potential microscopic disease. Initially, opposed lateral fields were used to treat the primary tumor and involved lymph nodes. Levels II to V nodes, along with the base of skull, were included in the initial treatment volume in most cases. Level I nodes were included in the field for oral cavity lesions. Most cases were treated with a three-field technique with a separate anterior field to treat uninvolved supraclavicular fossae to microscopic disease doses. Custom cerrobend blocks or multileaf collimators were used to shield areas that were not considered at risk of containing disease and to block critical structures to avoid exceeding tissue tolerance (eg, spinal cord). Each cycle of chemoradiotherapy consisted of 5 consecutive days of radiation with 1.5 Gy twice daily (3 Gy/d and 15 Gy/wk) in conjunction with chemotherapy. There was a minimum of 5 hours between fractions. Radiation therapy was delivered with a linear accelerator using 4 to 6 mV. Electrons were used to boost the posterior neck after 39 Gy to limit the dose to the spinal cord. Doses to the supraclavicular fossae were prescribed to a depth of 3 cm. A pseudoisocenter was selected for the prescription point of the opposed lateral fields. Multiple contours (at Northwestern University) or computed tomography–based three-dimensional treatment planning (at University of Chicago) were used to determine whether wedges, tissue compensators, or segmented fields should be used to decrease inhomogeneity. Radiation doses for presumed microscopic disease were 51 to 63 Gy. All areas of gross disease were further boosted after field reduction to a total of 70 to 75 Gy.
Surgical Guidelines
Supportive Care/Quality of Life Prospective quality-of-life evaluation included the following well-validated instruments: Functional Assessment of Cancer Therapy–Head and Neck Version,30,31 Performance Status Scale for Head and Neck Cancer,32,33 and McMaster Radiotherapy Questionnaire,34 which assesses patients’ perception of treatment-related side effects.35,36 Patients were assessed before treatment, during treatment, and at 3-month intervals after treatment (through 12 months),36 with long-term follow-up at 2 to 4 years after treatment completion.
Adjuvant Chemoprevention
Dose Modifications The dose of cisplatin was reduced to 50% if the calculated creatinine clearance level was 30 to 50 mL/min. No cisplatin was administered if the creatinine clearance level was less than 30 mL/min. The creatinine clearance level was calculated according to the formula of Cockcroft and Gault.37 For grade 3 toxicity that was believed to be the result of CRA, the drug was withheld until resolution of toxicity to grade 1 and then restarted at 25%. For grade 3 toxicity related to IFN, the drug was withheld until resolution of toxicity to grade 1 and restarted at a dose of 3 million units three times weekly. If grade 3 toxicity was again seen, IFN was discontinued.
Pharmacokinetic and Pharmacodynamic Evaluation
Statistical Evaluation The response rate was expressed as the proportion of patients who demonstrated complete and/or partial response. Time to progression was measured as the time from the first day of therapy until death of disease or toxicity, appearance of new lesions, or a greater than 25% increase of the indicator lesion over the previous smallest size. Survival was measured from the date of entry onto the study until death of any cause. Time to progression and survival time were summarized using Kaplan-Meier product limit curves. Quality-of-life data were summarized using the mean, SD, and percentage of patients who scored above or below a specified value that indicated moderate-to-severe dysfunction.33,35 Change over time was examined using paired t tests or McNemar test.
This study opened in September 1993 and was closed to patient accrual in February 1996. Follow-up is available through January 1999. Patients were entered at three participating institutions. The pretreatment patient characteristics are listed in Table 1. A total of 76 patients were entered; all but three had a performance status of 0 or 1. Seventy-one patients had stage IV disease, and only five had stage III disease. The most commonly involved primary sites included the oral cavity, oropharynx (53%), hypopharynx, and supraglottic larynx. Only one patient had nasopharyngeal cancer. Exact T and N stages are outlined in Table 2. Forty-six percent of patients had T4 disease, 54% had stage N2, and 21% had stage N3.
Response Fifty-one patients (67%; 95% confidence interval, 58% to 78%) had clinical complete response. Five of these were found to have residual microscopic disease at surgical reevaluation. Fourteen patients (18%) had clinical partial response; however, eight of these patients were found to be free of disease on pathologic review of neck dissection and/or biopsy of the primary site. Ten patients were not evaluated for response, including four (5.2%) who died while on therapy and six who had no measurable disease as a result of the use of initial debulking surgery.
Toxicities
Despite this acute toxicity, most patients completed their chemoradiotherapy regimen at or near intended doses (Table 4). This was facilitated by the administration of intensive supportive care. Ninety-six percent of patients had feeding support devices, 82% received RBC transfusions, and 53% received platelet transfusions. The intended and actual administered doses for all three drugs are summarized in Table 4. As is shown, the majority of patients received 80% or more of the intended dose of cisplatin, 5-FU, hydroxyurea, and radiotherapy.
Surgery Nine patients underwent initial surgery at the primary sites with neck dissection (Table 5). This consisted of debulking or diagnostic procedures in six patients and a partial glossectomy in three. Seventeen patients underwent neck dissection before the initiation of chemoradiotherapy. After completion of chemoradiotherapy, four patients underwent surgery at the primary site, which included glossectomy in one patient; only one of these had residual microscopic disease. Twenty-two patients had neck dissection; eight of these had residual microscopic disease, whereas 14 had no detectable residual cancer. Few patients underwent traditional surgical procedures at diagnosis or at any time after registration onto the protocol. Overall, only four patients underwent partial glossectomy, and one patient had a laryngectomy that was necessitated by the development of a fistula after the completion of chemoradiotherapy.
Adjuvant Chemoprevention The administration of adjuvant CRA and IFN proved challenging. Overall, only 13 patients received chemoprevention for more than 6 months, and 23 received it for less than 6 months (most of these received chemoprevention for less than 1 month). A total of 34 patients refused adjuvant chemoprevention altogether.
Outcome
Pharmacokinetics Among the 76 patients entered onto this trial, 5-FU plasma concentration was observed in 48 and DPD activity was observed in 29. There was no statistical difference in 5-FU plasma concentration or DPD activity between patients with complete response and those with partial response to chemotherapy. Steady-state 5-FU plasma concentration was not significantly different in patients who developed disease recurrence compared with patients with continued locoregional and distant disease control. Likewise, no difference in 5-FU plasma concentration or DPD activity was identified in patients with distant failure compared with those with locoregional failure.
Chronic Toxicities/Quality of Life and Performance Assessment
Despite performance deficits and the severity (based on the Functional Assessment of Cancer Therapy) of side effects, there was little change in patients’ emotional or social well-being (Table 8). Physical and functional well-being and overall quality of life declined on treatment but had fully recovered by 12 months (there were no significant differences between pretreatment and on-treatment values). These results have been published previously and discussed in greater detail.3
In this phase II study, we aimed at providing locoregional and distant disease control as well as chemoprevention for patients with advanced head and neck cancer. In this cohort of 76 patients, over 90% of whom had stage IV disease, we demonstrate that combining cisplatin, 5-FU, and hydroxyurea with twice daily (protracted) radiotherapy can result in a locoregional control rate that exceeds 90%. This exceedingly high locoregional control rate was achieved despite the minimal use of surgery. Overall, only 7% of patients underwent traditional surgery at the primary site. Thus, this C-FHX regimen allows for curative-intent therapy with preservation of the primary site. Of interest, the high locoregional activity is achieved despite the administration of chemoradiotherapy every other week. This finding further solidifies the evidence that protraction of radiotherapy in the presence of concomitant chemotherapy is not detrimental.16,17,21-27,39,40 Encouraging overall survival data are also reported. However, survival is impacted by a significant proportion of patients who develop distant disease and second malignancies and by a high incidence of deaths resulting from other medical conditions. These findings point out goals and directions for future investigations. It has long been hypothesized that, with improved locoregional control, systemic disease might emerge as an important clinical problem in head and neck cancer patients. This hypothesis is based on observations from autopsy series that indicate a high incidence of distant micrometastases in patients with advanced-stage head and neck cancer41 and seems to be supported by the findings reported in our study. With a locoregional control rate exceeding 90%, approximately 20% of patients were noted to recur distantly, despite the addition of cytotoxic chemotherapy to radiation therapy in this program. Because randomized clinical trials have indicated the ability of induction chemotherapy to successfully eradicate micrometastatic disease, it may be hypothesized that the addition of induction chemotherapy to concomitant chemoradiotherapy may be necessary if distant failure rates are to be further decreased. The integration of recently identified cytotoxic drugs with single-agent activity in head and neck cancer or of novel cytostatic agents into such induction chemotherapy regimens might also be pursued. This includes gemcitabine and the taxanes, topoisomerase I inhibitors, and novel agents that are directed at the epidermal growth factor receptor pathway or at inhibitors of angiogenesis. It is also clear that the strategies used in this study to address second malignancies were not practical. This seems to be largely a result of the unwillingness of patients to participate, at least using this particular adjuvant chemoprevention regimen. This is similar to the previously noticed poor compliance of patients undergoing adjuvant chemotherapy for advanced head and neck cancer. In our study, this may have been particularly exacerbated by the use of subcutaneously administered interferon, which frequently required extensive patient education and motivation. Simpler and less toxic chemopreventive regimens will be necessary. Regarding acute toxicities, it is clear that the C-FHX regimen resulted in frequently severe mucositis, dermatitis, and myelosuppression. Thus, further intensification of chemoradiotherapy to increase systemic cytotoxicity does not seem feasible. The identification of less toxic regimens and improved supportive care measures is a high priority. We have pursued this goal by eliminating cisplatin from the chemoradiotherapy regimen and adding paclitaxel to 5-FU and hydroxyurea.42 In recent years, radiation protective agents have been identified, including amifostine, interleukin-11, granulocyte macrophage colony-stimulating factor, and keratinocyte growth factor.43 Whether some of these agents will allow for protection of normal tissues without protecting the tumor is being addressed in clinical trials. Although organ preservation was achieved in the majority of our patients, a percentage of patients were not fully functional at completion of therapy. It is unclear at this time whether this relates to the destruction of the primary organ by the tumor before therapy or the administration of intensive hyperfractionated chemoradiotherapy. Our limited functional assessments do indicate that the majority of patients had reasonable speech and swallowing performance. Quality-of-life analysis further suggests that surviving patients had reasonable quality of life 1 year after the completion of chemoradiotherapy and beyond. Quality-of-life and functional parameters need to be included in the design and analysis of aggressive chemoradiotherapy and organ-preservation trials. Regarding the use of surgery, it is of interest that the majority of patients achieved locoregional control without the use of surgery. It is furthermore reassuring that the administration of surgery after the completion of concomitant chemoradiotherapy to 75 Gy was feasible. As we have reported previously, the complications from surgical interventions after chemoradiotherapy are low and would support a therapy sequence of concomitant chemoradiotherapy followed by surgical salvage if necessary.44 This observation may be a result of the timing of surgery within a defined window after the completion of chemoradiotherapy, thus preceding the manifestation of severe radiation-induced fibrosis. Pharmacokinetic evaluation of 5-FU has been shown to correlate with toxicity and response in patients who receive the drug (with cisplatin) in the induction setting.45-47 It seems that steady-state 5-FU plasma concentrations are not predictive of response or toxicity in patients who undergo this three-drug regimen with concomitant radiation. Similarly, activity of DPD, the rate-limiting enzyme in 5-FU catabolism, does not correlate with response or toxicity in this setting. Alternative molecular parameters might be of greater value. In summary, we demonstrate that the administration of hyperfractionated radiotherapy with concurrent cisplatin, 5-FU, hydroxyurea, and granulocyte colony-stimulating factor support is feasible and allows for high locoregional control with preservation of the primary site and with encouraging survival rates. Acute toxicities and long-term functional parameters indicate the need to identify less toxic chemoradiotherapy when pursuing organ-preservation strategies. Although we do not recommend the further investigation of the C-FHX regimen as defined here, we do think that the high locoregional control rate and feasibility of organ preservation support this general approach. We are currently evaluating chemoradiotherapy regimens in which paclitaxel is substituted for cisplatin. The determination of the pattern of failure and the integration of quality-of-life and functional assessments of our patients emerge as a clinical end point for these chemoradiotherapy studies.
Supported in part by National Institute of Health grants no. P30-CA14599 and P50 DE/CA 11921, the Geraldi-Norton Memorial Corporation, Northfield, IL, Amgen, Inc, Thousand Oaks, CA, Hoffmann-LaRoche, Nutley, NJ, and the Duchossois family. We acknowledge Michelle Tranchina for assistance in the preparation of the article, Mark Kozloff, MD, J. Nautiyal, MD, and William Moran, MD, for treating their patients on this protocol, Mark J. Ratain, MD, for supervision of pharmacokinetic analyses, and Alfred W. Rademaker for supervision of the statistical analysis.
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Vokes EE, Ratain MJ, Mick R, et al: Cisplatin, fluorouracil, and leucovorin augmented by interferon alfa-2b in head and neck cancer: A clinical and pharmacologic analysis. J Clin Oncol 11:360-368, 1993 Submitted July 16, 1999; accepted December 15, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
